Therapeutic quinoline and naphthalene derivatives

ABSTRACT

Disclosed herein is a stable compound having a structure: 
     
       
         
         
             
             
         
       
     
     therapeutic methods, compositions, and medicaments related thereto are also disclosed.

CROSS REFERENCE

This is a continuation application of U.S. application Ser. No.12/674,180, filed Oct. 22, 2010, which is a national stage applicationunder 35 U.S.C. §371 of PCT patent application PCT/US 2008/073798, filedon Aug. 21, 2008, which claims the benefit of U.S. Provisional PatentApplication 60/957,281 filed Aug. 22, 2007, each of which is herebyincorporated by reference in its entirety.

BACKGROUND

Sphingosine is a compound having the chemical structure shown in thegeneral formula described below, in which Y¹ is hydrogen. It is knownthat various sphingolipids, having sphingosine as a constituent, arewidely distributed in the living body including on the surface of cellmembranes of cells in the nervous system.

A sphingolipid is one of the lipids having important roles in the livingbody. A disease called lipidosis is caused by accumulation of aspecified sphingolipid in the body. Sphingolipids present on cellmembranes function to regulate cell growth; participate in thedevelopment and differentiation of cells; function in nerves; areinvolved in the infection and malignancy of cells; etc. Many of thephysiological roles of sphingolipids remain to be solved. Recently thepossibility that ceramide, a derivative of sphingosine, has an importantrole in the mechanism of cell signal transduction has been indicated,and studies about its effect on apoptosis and cell cycle have beenreported.

Sphingosine-1-phosphate is an important cellular metabolite, derivedfrom ceramide that is synthesized de novo or as part of thesphingomeyeline cycle (in animals cells). It has also been found ininsects, yeasts and plants.

The enzyme, ceramidase, acts upon ceramides to release sphingosine,which is phosphorylated by sphingosine kinase, a ubiquitous enzyme inthe cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate.The reverse reaction can occur also by the action of sphingosinephosphatases, and the enzymes act in concert to control the cellularconcentrations of the metabolite, which concentrations are always low.In plasma, such concentration can reach 0.2 to 0.9 μM, and themetabolite is found in association with the lipoproteins, especially theHDL. It should also be noted that sphingosine-1-phosphate formation isan essential step in the catabolism of sphingoid bases.

Like its precursors, sphingosine-1-phosphate is a potent messengermolecule that perhaps uniquely operates both intra- andinter-cellularly, but with very different functions from ceramides andsphingosine. The balance between these various sphingolipid metabolitesmay be important for health. For example, within the cell,sphingosine-1-phosphate promotes cellular division (mitosis) as opposedto cell death (apoptosis), which it inhibits. Intracellularly, it alsofunctions to regulate calcium mobilization and cell growth in responseto a variety of extracellular stimuli. Current opinion appears tosuggest that the balance between sphingosine-1-phosphate and ceramideand/or sphingosine levels in cells is critical for their viability. Incommon with the lysophospholipids, especially lysophosphatidic acid,with which it has some structural similarities, sphingosine-1-phosphateexerts many of its extra-cellular effects through interaction with fivespecific G protein-coupled receptors on cell surfaces. These areimportant for the growth of new blood vessels, vascular maturation,cardiac development and immunity, and for directed cell movement.

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular disease.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

Fungi and plants have sphingolipids and the major sphingosine containedin these organisms has the formula described below. It is known thatthese lipids have important roles in the cell growth of fungi andplants, but details of the roles remain to be solved.

Recently it has been known that derivatives of sphingolipids and theirrelated compounds exhibit a variety of biological activities throughinhibition or stimulation of the metabolism pathways. These compoundsinclude inhibitors of protein kinase C, inducers of apoptosis,immuno-suppressive compounds, antifungal compounds, and the like.Substances having these biological activities are expected to be usefulcompounds for various diseases.

DESCRIPTION OF THE INVENTION

Disclosed herein is a stable compound having a structure:

-   wherein n is 0, 1, or 2;-   m is 1 or 2;-   o is from 0 to 5;-   one of R¹ and R² has a formula    C₁₋₉H₀₋₂₃N₀₋₄O₀₋₄S₀₋₄F₀₋₆Cl₀₋₄Br₀₋₄I_(0-4,) and is selected from: a    substituted or unsubstituted heterocycle having 5 or 6 atoms in the    ring; and Cy, —S-Cy, —NH-Cy, and —O-Cy, wherein Cy is a substituted    or unsubstituted carbocycle or a substituted or unsubstituted    heterocycle;-   one of R¹ and R² is hydrogen or a substituent having a formula    C₀₋₁₂H₀₋₂₆N₀₋₂O₀₋₄S₀₋₁P₀₋₁F₀₋₆Cl₀₋₁Br₀₋₁I₀₋₁;-   each R³, R⁴, and R⁵ are independently a substituent having a formula    C₀₋₁₂H₀₋₂₆N₀₋₂O₀₋₄S₀₋₁P₀₋₁F₀₋₆Cl₀₋₁Br₀₋₁I₀₋₁;-   Y is N or C—H or C—R⁴;-   X is O, S, NH, N-alkyl having from 1 to 4 carbon atoms, or a bond;    and-   Z is hydrocarbyl having a formula C₁₋₈H₄₋₁₇.

These compounds are useful for the treatment of diseases or conditionssuch as glaucoma, dry eye, angiogenesis, cardiovascular conditions anddiseases, wounds, and pain. The compound is incorporated into a dosageform or a medicament and administered to the mammal, such as a person,in need thereof. Different types of suitable dosage forms andmedicaments are well known in the art, and can be readily adapted fordelivery of the compounds disclosed herein.

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the use of a compound, composition, therapeutically activeagent, or drug in the diagnosis, cure, mitigation, treatment, orprevention of disease or other undesirable condition.

Stable means that a compound is sufficiently stable to be stored in abottle at room temperature under a normal atmosphere for at least 12hours, or stable enough to be useful for any purpose disclosed herein.

Unless otherwise indicated, reference to a compound should be construedbroadly to include pharmaceutically acceptable salts, prodrugs,tautomers, alternate solid forms, non-covalent complexes, andcombinations thereof, of a chemical entity of the depicted structure orchemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A prodrug is a compound which is converted to a therapeutically activecompound after administration. For example, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion.

Unless stereochemistry is explicitly depicted, a structure is intendedto include every possible stereoisomer, both pure or in any possiblemixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

Heterocycle is a substituted or unsubstituted ring having at least oneatom in the ring selected from N, O, and S. A heterocycle may bearomatic or non aromatic. An aromatic heterocycle is also calledheteroaryl.

Carbocycle is a substituted or unsubstituted ring wherein all of theatoms in the ring are carbon. Examples include phenyl, cycloalkyl, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, etc.

A substituted ring or moiety means that a hydrogen is replaced with asubstituent. For example, a substituted carbocycle or heterocycle has asubstituent directly attached to the ring instead of hydrogen.

R¹, R², R³, R⁴, and R⁵ are all substituents. Examples of substituentsmay include the following subject to the constraints defined herein forthat particular moiety or substituent:

-   -   A. Hydrocarbyl, meaning a moiety consisting of carbon and        hydrogen only, including, but not limited to:        -   1. alkyl, such as:            -   linear alkyl, i.e. a moiety consisting of carbon and                hydrogen having no double bonds, e.g. methyl, ethyl,                n-propyl, n-butyl, n-pentyl, n-hexyl, etc.,            -   branched alkyl, e.g. iso-propyl, t-butyl and other                branched butyl isomers, branched pentyl isomers, etc.,            -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,                cyclohexyl, etc.,            -   combinations of linear, branched, and/or cycloalkyl;        -   2. alkenyl, e.g. hydrocarbyl having 1 or more double bonds,            including linear, branched, or cycloalkenyl        -   3. alkynyl, e.g. hydrocarbyl having 1 or more triple bonds,            including linear, branched, or cycloalkynyl;.        -   4. combinations of alkyl, alkenyl, and/or akynyl    -   B. alkyl-CN, such as —CH₂—CN, —(CH₂)₂—CN; —(CH₂)₃—CN, and the        like;    -   C. Hydroxy, —OH    -   D. hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl,        hydroxyethyl, and the like;    -   E. ether substituents, including —O-alkyl, alkyl-O-alkyl, and        the like;    -   F. thioether substituents, including —S-alkyl, alkyl-S-alkyl,        and the like;    -   G. amine substituents, including —NH₂, —NH-alkyl,        —N-alkyl¹alkyl² (i.e., alkyl¹ and alkyl² are the same or        different, and both are attached to N), alkyl-NH₂,        alkyl-NH-alkyl, alkyl-N-alkyl¹alkyl², and the like;    -   H. aminoalkyl, meaning alkyl-amine, such as aminomethyl        (—CH₂-amine), aminoethyl, and the like;    -   I. ester substituents, including —CO₂-alkyl, —CO₂₋phenyl, etc.;    -   J. other carbonyl substituents, including aldehydes; ketones,        such as acyl, including, acetyl, propionyl, and benzoyl        substituents are contemplated;    -   K. fluorocarbons or hydroflourocarbons such as —CF₃, —CH₂CF₃,        etc.; and    -   L. other nitrogen containing substituents such as —CN and —NO₂,    -   M. other sulfur containing substituents such as sulfide,        sulfonyl or sulfoxide;    -   N. aryl;    -   O. combinations of the above are also possible, subject to the        constraints defined;    -   P. Alternatively, a substituent may be —F, —Cl, —Br, or —I.

In one embodiment, R¹, R², R³, R⁴, and R⁵ are moieties having no Cl, Br,or I, unless the Cl, Br, or I is attached directly to a carbon of anaromatic ring. In other words, if R¹, R², R³, R⁴, or R⁵ contain Cl, Br,or I, the moiety either consists of —Cl, —Br, or —I; or is an aromaticor heteroaromatic ring having —Cl, —Br, or —I directly bonded to acarbon atom of the ring.

Aryl is any substituted or unsubstituted aromatic or heteroaromatic ringor ring system. Some examples of aryl include substituted orunsubstituted benzenes, pyridines, pyrazines, pyridazines, pyrimidines,triazines, thiophenes, furans, thiazoles, thiadiazoles, isothiazoles,oxazoles, oxadiazoles, isooxazoles, naphthalenes, quinolines, tetralins,chromans, thiochromans, tetrahydroquinolines, dihydronaphthalenes,tetrahydronaphthalenes, chromenes, thiochromenes, dihydroquinolines,indans, dihydrobenzofurans, dihydrobenzothiophenes, indenes,benzofurans, benzothiophenes, coumarins, coumarinones, and the like.

Hydrocarbyl substituted methylene is

where each R10 is independently H or hydrocarbyl.

The formula C₁₋₉H₀₋₂₃N₀₋₄O₀₋₄S₀₋₄P₀₋₆Cl₀₋₄Br₀₋₄I₀₋₄ means that themoiety of that formula is composed of the following atoms:

-   -   from 1 to 9 carbon atoms;    -   from 0 to 23 hydrogen atoms;    -   from 0 to 4 nitrogen atoms;    -   from 0 to 4 oxygen atoms;    -   from 0 to 4 sulfur atoms;    -   from 0 to 6 fluorine atoms;    -   from 0 to 4 chlorine atoms;    -   from 0 to 4 bromine atoms; and    -   from 0 to 4 iodine atoms.

Similarly, the formula C₀₋₁₂H₀₋₂₆N₀₋₂O₀₋₄S₀₋₁P₀₋₁P₀₋₁Cl₀₋₁Br₀₋₁I₀₋₁means that the moiety of that formula is composed of the followingatoms:

-   -   from 0 to 12 carbon atoms;    -   from 0 to 26 hydrogen atoms;    -   0 or 2 nitrogen atoms;    -   from 0 to 4 oxygen atoms;    -   0 or 1 sulfur atoms;    -   0 or 1 phosporous atoms;    -   from 0 to 6 fluorine atoms;    -   0 or 1 chlorine atoms;    -   0 or 1 bromine atoms; and    -   0 or 1 iodine atoms.

Similarly, the formula C₁₋₈H₄₋₁₇ means that the moiety of that formulais composed of the following atoms:

-   -   from 1 to 8 carbon atoms; and    -   from 4 to 17 hydrogen atoms;

If a chemical species is an ion, only the atoms covalently attached toother atoms of a formula are counted. For example, if the species is acarboxylate associated with a sodium counter-ion, the sodium is notcounted as part of the formula, or if the species is an ammonium ionassociated with a chloride counter-ion, the chlorine is not counted aspart of the formula.

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, o is 2.

In another embodiment, o is 3.

In another embodiment, o is 4.

In another embodiment, o is 5.

In one embodiment, an R⁵ is a straight or branched chain alkyl, aryl,alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy, alkylhydroxy(-alkyl-OH), alkylcarbonyl (—C(O)-alkyl), formyl, oxycarbonyl(—OC(O)-hydrocarbyl), carboxyl, alkyl carboxylate (—CO₂-alkyl), alkylamide, aminocarbonyl (—NR₂C(O)-hydrocarbyl, where R is hydrocarbyl),amino, cyano, diazo, nitro, phosphate, thio, sulfoxyl(—S(O)-hydrocarbyl), or sulfonyl (—S(O)₂-hydrocarbyl).

In another embodiment, each R⁵ is indepedently a straight or branchedchain alkyl, aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy,alkylhydroxy (-alkyl-OH), alkylcarbonyl (—C(O)-alkyl), formyl,oxycarbonyl (—OC(O)-hydrocarbyl), carboxyl, alkyl carboxylate(—CO₂-alkyl), alkyl amide, aminocarbonyl (—NR₂C(O)-hydrocarbyl, where Ris hydrocarbyl), amino, cyano, diazo, nitro, phosphate, thio, sulfoxyl(—S(O)-hydrocarbyl), or sulfonyl (—S(O)₂-hydrocarbyl).

In another embodiment, an R³ is a straight or branched chain alkyl,aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy, alkylhydroxy,alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, aminocarbonyl, amino, cyano, diazo, nitro, phosphate, thio,sulfoxyl, sulfonyl, or a group selected from:

In another embodiment, each R³ is a straight or branched chain alkyl,aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy, alkylhydroxy,alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, aminocarbonyl, amino, cyano, diazo, nitro, phosphate, thio,sulfoxyl, sulfonyl, or a group selected from:

In another embodiment, an R⁴ is a straight or branched chain alkyl,aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy, alkylhydroxy,alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, aminocarbonyl, amino, cyano, diazo, nitro, phosphate, thio,sulfoxyl, sulfonyl, or a group selected from:

In another embodiment, each R⁴ is a straight or branched chain alkyl,aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxy, alkylhydroxy,alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, aminocarbonyl, amino, cyano, diazo, nitro, phosphate, thio,sulfoxyl, sulfonyl, or a group selected from:

R¹ and R² are different. One of the two one of R¹ and R² has a formulaC₁₋₉H₀₋₂₃N₀₋₄O₀₋₄S₀₋₄F₀₋₆Cl₀₋₄Br₀₋₄I₀₋₄, and is selected from: asubstituted or unsubstituted heterocycle having 5 or 6 atoms in thering; and Cy, —S-Cy, —NH-Cy, and —O-Cy, wherein Cy is a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle.

The other R¹ and R² is hydrogen, or is subject to the same constraintsas R³, R⁴, and R⁵.

In other words, the structures below are contemplated, where q is from 0to 3, Hy is a substituted or unsubstituted heterocycle having 5 or 6atoms in the ring, and Hy, Cy, —S-Cy, —NH-Cy, and —O-Cy have the formulaC₁₋₉H₀₋₂₃N₀₋₄O₀₋₄S₀₋₄F₀₋₆O₀₋₄Br₀₋₄I₀₋₄.

Some examples of Hy include the following:

Some examples of Cy include the following:

In one embodiment, one of R¹ and R² has a formulaC₁₋₉H₀₋₂₃N₀₋₄O₀₋₄S₀₋₄F₀₋₆, and is selected from: a substituted orunsubstituted heterocycle having 5 or 6 atoms in the ring; and Cy,—S-Cy, —NH-Cy, and —O-Cy, wherein Cy is a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle.

Y is N, C—H or C—R⁴. Thus, compounds having structures such as thosebelow are contemplated.

X is O, S, NH, N-alkyl having from 1 to 4 carbon atoms, or a bond. Thus,compounds having structures such as those below are contemplated.

Z is hydrocarbyl having a formula C₁₋₈H₄₋₁₇. Thus, compounds havingstructures such as those below are contemplated.

In one embodiment, Z is C₁₋₈ alkyl.

One embodiment is a compound represented by the structure:

-   wherein R³⁰ is phenyl, heteroaryl, or t-butyl;-   R⁴⁰ is C₁₋₆ alkyl, C₁₋₇ carboxylate, or C₁₋₇ alkylcarbonyl; and-   Cy is a substituted or unsubstituted carbocycle or a substituted or    unsubstituted heterocycle.

Compounds according to one of the structures below, wherein R²⁰ is C1-6alkyl, are contemplated.

Hypothetical examples of useful compounds are shown below.

On example of a general method to prepare these compounds is describedin Scheme 1.

Compounds A and B are purchased or prepared using conventional methods.These compounds are condensed to the quinolinyl core structure (CompoundC) by treating with a base, followed by an acid catalyst. The methoxymoiety of A and C acts as a precursor to either R¹ or R², depending uponwhich has the O-Cy structure. The methoxy is removed, and the Cy- moietyis added via a conventional nucleophilic substitution reaction toproduce D. Alternatively, a protected nitrogen or sulfur atom may beused to yield the —S-Cy, or —NH-Cy moiety. The ester of D is thencleaved and added to E to obtain the final compound F.

The naphthyl analog of C may be prepared by oxidizing the correspondinghydroxyl naphthaldehyde and adding E as in Scheme 1. Methods ofpreparing these compounds are known, for example, Chamontin, et. al.(Tetrahedron 55 (1999) 5821-5830) provides a method that may be used.

One hypothetical example of use of the method of Scheme 1 is depicted inScheme 2 below.

These compounds may be assessed for their ability to activate or blockactivation of the human S1P3 receptor in T24 cells stably expressing thehuman S1P3 receptor by the following procedure. Ten thousand cells/wellare plated into 384-well poly-D-lysine coated plates one day prior touse. The growth media for the S1P3 receptor expressing cell line isMcCoy's 5A medium supplemented with 10% charcoal-treated fetal bovineserum (FBS), 1% antibiotic-antimycotic and 400 μg/ml geneticin. On theday of the experiment, the cells are washed twice with Hank's BalancedSalt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer). Thecells are then dye loaded with 2 uM Fluo-4 diluted in the HBSS/Hepesbuffer with 1.25 mM Probenecid and incubated at 37° C. for 40 minutes.Extracellular dye is removed by washing the cell plates four times priorto placing the plates in the FLIPR (Fluorometric Imaging Plate Reader,Molecular Devices). Ligands are diluted in HBSS/Hepes buffer andprepared in 384-well microplates. The positive control,Sphingosine-1-Phosphate (S1P), is diluted in HBSS/Hepes buffer with 4mg/ml fatty acid free bovine serum albumin. The FLIPR transfers 12.5 μlfrom the ligand microplate to the cell plate and takes fluorescentmeasurements for 75 seconds, taking readings every second, and then for2.5 minutes, taking readings every 10 seconds. Drugs are tested over theconcentration range of 0.61 nM to 10,000 nM. Data for Ca⁺² responses areobtained in arbitrary fluorescence units and not translated into Ca⁺²concentrations. IC₅₀ values are determined through a linear regressionanalysis using the Levenburg Marquardt algorithm.

What is claimed is:
 1. Use of a compound selected from the following inthe manufacture of a medicament for the treatment of a disease orcondition in a mammal, said disease or condition selected from glaucoma,dry eye, angiogenesis, cardiovascular conditions and diseases, wounds,and pain:


2. The use of claim 1 wherein the mammal is a human.
 3. A method oftreating a disease or condition comprising administering a compoundaccording to claim 1 to a mammal in need thereof, said disease orcondition selected from glaucoma, dry eye, angiogenesis, cardiovascularconditions and diseases, wounds, and pain.
 4. The method of claim 3wherein the mammal is a human.
 5. A method of treating a disease orcondition comprising administering to a mammal in need thereof, at leastone compound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein said disease or condition is selected from the groupconsisting of glaucoma, dry eye, angiogenesis, cardiovascular conditionsand diseases, wounds, and pain.
 6. The method of claim 5 wherein themammal is a human.
 7. A method of treating a disease or conditioncomprising administering to a mammal in need thereof, at least onecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein said disease or condition is selected from the groupconsisting of glaucoma, dry eye, angiogenesis, cardiovascular conditionsand diseases, wounds, and pain.
 8. The method of claim 7 wherein themammal is a human.